Neovascularization is the formation of new blood vessels—generally capillary ingrowth or endothelial proliferation—in unusual sites. The phenomenon is typical of so-called angiogenic diseases, which include angiogenesis in tumor growth. Recently, it has been determined that neovascularization can also occur in arterial plaques. Thus, during atherosclerosis development, reduction of the oxygen supply to the vessel wall may occur, resulting in ischemia, which induces a continual release of growth factors that stimulate the neovascularization processes. These immature neovessels tend to leak and increase the plaque volume, which encourages the ongoing process of neovascularization and the generation of “vulnerable” plaques. Vulnerable plaques, which are also known as “thrombosis-prone plaques,” have a high probability of undergoing rupture and causing local thrombosis and embolism, thus leading to stroke. Because of its importance in determining cerebral functionality, the status of the carotid artery is especially important, and carotid atherosclerosis has become recognized as an important factor in the pathogenesis of cerebral events. Some known causes of plaque vulnerability are large lipid core, thin fibrous cap, and calcifications. However, neovascularization and inflammation are generally considered the main causes of atherosclerotic plaque vulnerability and rupture. Inflammatory cells tend to continuously destabilize the plaque by eroding the fibrous cap. This erosion may cause a rupture of the vulnerable plaque, which stimulates platelet aggregation and intravascular thrombosis. A thrombus may detach from the area of the plaque, flow within the internal carotid and block a smaller vessel within the brain Therefore, indication for, for instance, carotid endarterectomy, which is commonly based on the degree of stenosis (>70%), may be insufficient, and risk evaluation based on the plaque composition would be valuable in the treatment decision process. Thus, a noninvasive imaging method to enable the assessment of plaque vulnerability on the basis of plaque vascularization would be highly desirable.
Furthermore, in the treatment of cancerous tumors, many drug therapies operate by attempting to diminish the blood supply to the tumor. Therefore, in common with the above described situation for plaque neovascularization, the quantitative assessment of neovascularization within a tumor is also an important objective which could provide important information for monitoring the treatment of such tumors, and for evaluating potential hazards related to the potential growth of the tumor.
Existing solutions for evaluating the overall size of a tumor or plaque, are generally limited to the determination of some total average of the vasculature dimensions, and are mostly based on ultrasound grey-level imaging using injected contrast agents. However, such a method does not allow any visualization of the vasculature itself. Ultrasound Doppler and Power Doppler technologies do allow imaging of flow, but their spatial resolution is low, since long duration pulses are required. Thus the spatial resolution and the level of information that can be obtained from quantification based on the currently used technologies is limited. Other imaging modalities such as MRI or CT, do not have sufficient resolution to provide specific information about very small blood vessels, besides being less available than ultrasound.
In order to efficiently monitor changes in the vasculature within a tumor or a plaque, it is necessary to identify the vascular tree and to specifically measure its true effective area/volume. The level of quantification currently attained is limited. Neovascularization within plaques has been measured recently, but currently there has been no report of performing this measurement quantitatively. Current methods thus provide only a rough estimate of the amount of contrast agent within a specific area—but such a measure generally lacks the desired accuracy.
In previous studies, visual approaches or gray level averaging within the examined region of interest have been used to semi-quantify intraplaque neovascularization on such contrast-enhanced ultrasound images, usually by using a discrete, limited grading system. Several variations of such visual approach methods have been described in such patent documents as US 2003/0032880 to P. Moore, for Apparatus and Method for Ultrasonically Identifying Vulnerable Plaque, US 2008/0200815 to A. F. W Van Der Steen et al, for Intravascular Ultrasound Techniques, US 2008/007018 to M. E. Frijlink et al., for Pulse Inversion Sequences for Non-linear Imaging, U.S. Pat. No. 7,657,299 to J. L. Huizenga et al., for Automated Methods and Systems for Vascular Plaque Detection and Analysis, and U.S. Pat. No. 7,729,525 to E. Camus et al., for Imaging Evaluation Method for Two-Dimensional Projection Images and Items Corresponding Thereto.
Although such methods and systems provide a general assessment of the neovascularization burden, they lack an objective method for a fully quantitative analysis of neovascularization in atheromatous plaque or in tumorous tissue. There therefore exists a need for providing a method and system able to provide a quantitative measure of neovascularization within a plaque or a tumor, such that enables real time monitoring of the treatment applied to the subject. The carotid artery is a much studied artery and because of its importance, it would be a prime subject for implementing such a method and system. Neovascularization in plaques therein will therefore be generally used in this disclosure to illustrate exemplary implementations of the various aspects of the methods and systems described herewithin. It is to be understood, however, that it is not intended that the methods and systems described and claimed be limited to this specific example.
The disclosures of each of the publications mentioned in this section and in other sections of the specification, are hereby incorporated by reference, each in its entirety.